1. Field of the Invention
The present invention relates to a novel nonconventional liposome composition enabling an efficient loading and sustained release of steroidal drugs. The composition is particularly useful in formulating steroids for inhalation, targeted systemic, parenteral, and topical administration for human and veterinary therapeutic applications.
2. Related Disclosures
Steroids, in particular corticosteroids, have been found to have a wide repertoire of therapeutic applications. For pharmaceutical use, these steroids are synthesized as structural analogues of the adrenocortical hormone hydrocortisone. Corticosteroids have powerful effects on immunologic and hormonal processes, and are very effective in treating a wide range of inflammatory diseases, such as arthritis, rheumatoid arthritis, allergic reactions and conditions such as asthma, pulmonary fibrosis and other lung diseases, and are widely used for treatment of ophthalmic and dermatological irritations.
As with many potent drugs given systemically, the therapeutic benefits of corticosteroids are accompanied by an array of deleterious side effects, such as, among others, muscular atrophy, disruption of adrenal-pituitary axis resulting in stunted growth in children, edema, hypertension, osteoporosis, glaucoma, damage to the immune system leading to susceptibility to viral and fungal infections, psychological disorders, and even heart failure.
Attempts to minimize these complications were not very successful. For example, daily systemic administration of smaller, insufficient and inadequate doses of steroids for desired therapy, led to unsuccessful or prolonged treatments. On the other hand, an administration of the higher doses of steroids on alternate days led to peaks in the blood level of the steroid followed by the side effects. Both of these conditions were found to be highly undesirable.
Thus, it would be greatly advantageous to provide a pharmaceutical formulation which would allow slow but sustained release of steroids preferably only at the target organ.
Some improvements were achieved by focusing on administration of steroids via routes that diminish the systemic side effects elsewhere in the body, or by formulating them in delivery systems that might improve the benefit-to-toxicity therapeutic ratio. However, because of poor solubility in water, these attempts to formulate steroids in an appropriate vehicles for particular therapies have been in general unsuccessful.
Thus, it would be advantageous to have available a steroid composition formulated in such a way as to carry to and release in the particular organ in need of such therapy an effective dose for extended periods of time using the minimum amount of steroid. By solving such formulation challenges, that is, by developing an appropriate formulation vehicle for each therapy, the undesirable side effects accompanying steroid therapies would be diminished.
Some of the difficulties connected with steroid formulation are due to the fact that steroids are poorly soluble or insoluble in water. For that reason, methods previously used to obtain effective formulation have relied either on use of organic solvents or on crystalline suspensions in an aqueous medium. Organic solvents such as ethanol, butanol, propanol and others are prone to cause tissue irritation and may be painful when administered by certain routes.
To avoid the severe systemic side effects, commonly used and preferred route of administration of steroids for treatment of pulmonary conditions is via inhalation. However, the inhalation of normally formulated steroids leads to a rapid absorption, necessitating the more frequent dosing, which in turn, cause the heightening of systemic side effects. Notwithstanding, even the normally formulated steroidal inhalants are preferable for replacing systemically-administered steroids because they reduce, albeit not eliminate, the side effects when inhaled at recommended doses. The need for repeated dosing however, remains. That need can only be avoided by providing the formulation allowing for sustained controlled release of the steroid.
The advantage of inhalation administration of steroids over the systemic administration can best be illustrated using, for example, a potent anti inflammatory steroid dexamethasone. Dexamethasone is normally administered systemically by i.v. injection in doses ranging from 0.5 to 9 mg/day with even higher doses required in certain severe conditions. Where, however, dexamethasone is administered via inhalation, the dose is approximately 0.084 mg. The total dose of inhaled dexamethasone daily, even when the inhalation is repeated at the maximum dosing frequency, i.e. 12 times a day, corresponds to 0.4 to 0.6 mg to a maximum of around 1.0 mg of absorbed dexamethasone a day. PDR: 1312 and 1315 (1988). Beclomethasone, halogenated synthetic analog of cortisol used in a form of beclomethasone dipropionate (BDP) faces a similar problem. BDP is currently used for inhalation and as a nasal spray for treatment of bronchial asthma and seasonal and perenial rhinitis. Because beclomethasone dipropionate is poorly soluble in water, it is currently formulated as a microcrystalline suspension in halogenated alkane (Freon) propellants (PDR:1003 (1988).
The secondary adverse reactions following the use of these non-liposomal inhalers and sprays include localized infection of the mouth and pharynx with Candida albicans or Asperqillus niqer hoarseness and dry mouth. Simultaneous use of these steroids with other aerosols is not recommended due to potential toxicity from the inhaled fluorocarbon propellants. Further, tissue irritation has been reported due to drug crystallization and sedimentation during storage.
The advantages connected with using inhalation route rather than systemic administration are lessened by the necessity of multiple dosing. Such dosing is inconvenient, unpleasant, and may lead to nasal or oral mucosal tissue damage caused by repeated application of fluorocarbon, a drug carrying propellant, or by a solvent, or other additives necessary for nasal or oral inhalation administration.
Thus, it would be highly desirable to have a steroid formulation in the form of an inhalation system providing a sustained release of steroids where the number of inhalation administrations per day would be greatly reduced.
As pointed out above, steroids, due to their chemical structure are poorly soluble in aqueous systems. Thus, in order to formulate steroid in an aqueous solvent it is necessary to add solubilizing agents such as ionic surfactants, cholates, polyethylene glycol (PEG), ethanol, and other solubilizers or use micronized suspension of crystalline drug. While in general these agents are considered pharmaceutically acceptable excipients, many of them have undesirable side effects particularly when used in inhalation, nasal or topical formulations. The deleterious effect of agents such as PEG in membrane permeabilization and local irritation is well documented.
Therefore, it would be advantageous to provide steroid formulations without the necessity of adding such solubilizing agents and be able to generate submicron droplets by nebulization for deep lung penetration.
Certain improvements have previously been achieved by encapsulating steroids in conventional liposomes. For example, smaller doses of steroids were found to be effective when administered in liposome-encapsulated form. Also, modest prolongation of effect and restriction of the drug to the site of administration was achieved, and a marginal degree of decreased systemic uptake was accomplished.
Liposomes, lipid based drug carrier vesicles have recently emerged as a new technology in pharmaceutical sciences. Liposomes are composed of nontoxic, biodegradable lipids, in particular of phospholipids. Attempts have been made to prepare liposomes from nonphospholipid components which have the potential to form lipid bilayers that are more durable than conventional liposomes (Bioch. Biophys. Acta, Vol. 227-232 (1982)). Currently, both conventional and non-phospholipid liposomes are rapidly becoming accepted as pharmaceutical agents which improve the therapeutic value of a wide variety of compounds.
Liposome drug delivery systems are reviewed in detail in Cancer Res., 43:4730 (1983). In general, liposomes are advantageous in that they can provide controlled release of an entrapped drug, reduce side effects by limiting the concentration of free drug in the bloodstream, alter the tissue distribution and uptake of drugs in a therapeutically favorable way, and make therapy safer and more convenient by reducing the dose or frequency of drug administration.
Liposomes generally have been known to improve formulation feasibility for drugs, to provide prolonged sustained release, to reduce toxicity and to improve the therapeutic ratio, to prolong the therapeutic effect after each administration, to reduce the need for frequent administration, and to reduce the amount of drug needed and/or absorbed by the mucosal or other tissue.
Advantages such as decreased toxicity and degradation, use of smaller doses, the possibility of targeting the liposome towards a specific site, and reducing side effects of a liposome-bound cortisol over the use of a free or polymer-bound cortisol have been described in Nature. 271: 372-373 (1978).
The use of liposomes as a solubilizing agent for steroids in aqueous, nebulized inhalation suspensions essentially eliminates the use of potentially toxic halogenated hydrocarbon propellants and co-solvents such as ethanol. Such formulations also assure that the drug stays in a stable suspension, thus preventing the irritation caused by drug sedimentation and crystallization. Such irritation is often encountered with conventional steroidal suspension preparations. Notwithstanding the above, utilizing liposomes for inhalation formulations still face numerous problems. For example there is a little or no effect of liposomal entrapment on rapid systemic uptake, which remains unchanged indicating that even from the liposomes the steroid is still rapidly released.
Because of their poor formulation properties, many useful steroids have had to be derivatized or modified so they could be accommodated within the chemical structure of the liposomes for enhanced retention. For example, 6-18 carbon-chain ester needs to be present in the steroid molecule for optimal lipophilic interaction between the water-insoluble corticosteroid and the lipid membrane.
The necessity for steroid modification is addressed in EPO application 85850222.2, which describes increased binding of the steroid to the liposomal membrane by derivatizing said steroid with a hydrophobic anchor, such as a fatty acyl chain. While the binding of derivatized drug to the membrane was shown to be somehow improved, the steroid derivative still did not sufficiently slow efflux rates of steroid from liposomes. This was due to the fact that the lipid composition of conventional, phospholipid liposomes does not provide a strong enough barrier to slow down the release of the derivatized steroid and to achieve prolonged release. U.S. Pat. No. 4,693,999 discloses new steroid derivatives obtained by modification of corticosteroids, with fatty acid esters. These modified steroids incorporated in the lipid portion of liposomes for delivery via inhalation provided a prolonged steroid retention in the respiratory tract of experimental animals.
However, designing and synthesizing new steroid derivatives is inconvenient, costly, slow, laborious and often changes the drug efficacy. Thus, it would be greatly advantageous to provide a liposomal steroid formulation with substantially improved drug retention without need for drug modification.
Dexamelhasone palmitate, a modified synthetic analog of cortisol, incorporated in liposomes was shown to surpass the effectiveness of microcrystalline cortisol acetate injection into arthritic joints of experimental animals. J. Microencaosulation, 4:189-200 (1987). However, although the formulation itself provided enhanced therapy against inflammation and diminished the leakage levels of the steroid into systemic circulation, the formulation was not therapeutically suitable because the charged carrier, necessary for the liposome formulation, proved to have cytotoxic effects.
Nevertheless, many problems still remain unresolved with steroid formulations using conventional phospholipid liposomes. Some of these problems relate to the requirement for drug modification, poor drug loading into liposomes and poorly controlled release rate.
Water-insoluble steroids are generally difficult to load into conventional phospholipid liposomes because these molecules tend to crystallize rather than incorporate into the liposomal membrane. Such drug crystallization causes the same sedimentation problems and free drug toxicity upon administration as do non-liposomal steroidal suspensions. Modified steroids, unlike cholesterol which is ubiquitously distributed in biological membranes, in particular seem to be structurally or sterically incompatible with phospholipids in terms of hydrophobic or Van Der Waals interactions and thus crystallize out readily.
It would therefore be highly desirable to provide a formulation where the loading of the steroidal drug into liposomes would be improved and the crystallization problem avoided.
Previously available conventional liposomal steroidal formulations have also shown an uncontrollable and impractically fast release rate. Measurements of systemic uptake from the respiratory tract after inhalation of underivatized steroids formulated in conventional liposomes indicated little or no effect of liposomal entrapment on the release rate. This means that despite the liposome binding, the drug was still released relatively quickly from the conventional phospholipid liposomes. This may be due to the fact that all steroids which are lipophilic in their nature tend to be released from the lipid membrane faster than water-soluble drugs encapsulated in the liposomes. Biochem J., 158:473-6 (1976).
Thus, it would be greatly desirable to develop a pharmaceutically acceptable composition where the steroids could be formulated without the need of modifying or derivatizing the steroid itself, which at the same time could carry the greater amount of steroid and from which the steroid could be released with controllable and desired rate. The resulting composition would have to be capable of solubilizing the underivatized steroid, having highloading ability, prolonged sustained-release and stability.
It is the primary object of this invention to provide the liposome-steroid composition wherein the poorly water soluble or insoluble, sedimentation-prone, underivatized or unmodified steroids are successfully sequestered within the liposomal lipid vesicles of uniform and controllable particle size, having at the same time high encapsulation values, long-term stability, and effective sustained release with a controllable potency of the drug. The resulting composition would allow an administration of low doses of steroid thus reducing toxicity and systemic side effects while at the same time providing pharmacologically bioavailable doses of steroid in situ of the target organs. The composition would also be economically advantageous because it would effectively formulate all therapeutically needed steroid without loss occurring during the steroid formulation or during the therapeutical administration.